Biochemistry Of Ligand Gated Ion Channels

配体门控离子通道的生物化学

基本信息

  • 批准号:
    7149292
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

Nicotinic acetylcholine receptors, the ligand gated ion channels at which nicotine acts, play an important role in nicotine abuse and understanding its neurobiology may be central to developing more rational approaches for nicotine abuse treatments. The in vitro characterization of the receptor-ligand interaction is an important step in understanding the action of a ligand in vivo (i.e., for interpretation of the results from the functional studies of receptors). Recently, three radiohalogenated analogs of 3-(2(S)-azetidinylmethoxy)pyridine (A-85380) have been used successfully for the in vivo visualization of alpha4beta2* nicotinic receptors in the human brain with PET/SPECT. Previously we reported the characterization of one of these radioligands 5-[I-125]iodo-3-(2(S)-azetidinylmethoxy) pyridine. We performed an in vitro characterization of the second of these radioligands, 6-[F-18]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (6 [F-18]fluoro-A-85380. In human postmortem cortical tissue, 6-[F-18]fluoro-A-85380 reversibly binds with high affinity to a single population of sites (Kd =59 pM at 37?C, Bmax =0.7 pmol/g tissue). The binding is fully reversible and is characterized at 37 degrees C by a T? for the association of 2.2 min (at a ligand concentration of 39 pM) and by a T? for the dissociation of 3.6 min. 6-Fluoro-A-85380 exhibits clear selectivity for the alpha4beta2* subtype over the other major mammalian nicotinic receptor subtypes: alpha7, alpha3beta4, and muscle-type. These results suggest that 6 [F-18]fluoro-A-85380 is a promising radioligand for in vivo imaging of brain alpha4beta2* nicotinic receptors. Less upregulation of nicotinic acetylcholine receptors is found in studies of brain tissue from patients with schizophrenia who smoke than in brain tissue from mentally healthy smokers. As schizophrenic patients often take typical or atypical neuroleptics chronically, the impact of these drugs on the upregulation of alpha4beta2* nicotinic receptors by nicotine was tested in rats. Literature reports suggest that the typical neuroleptic, haloperidol, has no effect. We tested the effect of the atypical neuroleptics, risperidone and olanzapine on the upregulation of these receptors by nicotine in the thalamus, striatum and hippocampus of rats using in vitro assays with 5-[I-125]iodo-A-85380. Neither drug attenuated the effect of nicotine, which increased the density of the receptors in these areas by 50, 80 and 90%, respectively; however, risperidone given without nicotine produced a modest increase (25%) in the density of the nicotinic receptors in the striatum. Substantial anecdotal evidence suggests that nicotine may function as a gateway drug to illicit drug use. As such we utilized an animal behavorial model of drug rewards, conditioned place preference, (CPP) to test the hypothesis that nicotine produces behavioral cross-sensitization to different classes of abused drugs, specifically opiates, stimulants and marihuana. These experiments in rats demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nAChRs as the competitive alpha4beta2 antagonist dihydro beta erythroidine effectively blocked the development of nicotine-induced cross sensitization. Interestingly, the alpha7 nicotinic antagonist methyllycaconitine also antagonized cross-sensitization at doses that do not block nicotine self-administration in rats. This study and published report have clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both opiates and psychostimulants measured with CPP. The development of cross-sensitization to the rewarding effects of these drugs involves the interaction of nicotine with both alpha4beta2 and alpha7 nAChRs, which differs from niccotine self-adminiistratiiion, which is primarily mediated by alpha4beta2 receptors.
尼古丁乙酰胆碱受体是尼古丁作用的配体门控离子通道,在尼古丁滥用中起着重要作用,了解其神经生物学可能是开发更合理的尼古丁滥用治疗方法的关键。受体-配体相互作用的体外表征是理解配体体内作用的重要步骤(即,用于解释来自受体的功能研究的结果)。 最近,3-(2(S)-氮杂环丁烷甲氧基)吡啶(A-85380)的三种放射性卤代类似物已成功用于PET/SPECT对人脑中α 4 β 2 * 烟碱受体的体内显像。以前,我们报道了这些放射性配体之一5-[I-125]碘-3-(2(S)-氮杂环丁烷甲氧基)吡啶的表征。我们对第二种放射性配体6-[F-18]氟-3-(2(S)-氮杂环丁烷基甲氧基)吡啶(6 [F-18]氟-A-85380)进行了体外表征。在人死后皮质组织中,6-[F-18]fluoro-A-85380以高亲和力可逆结合于单个位点群体(37?C,Bmax =0.7 pmol/g组织)。的结合是完全可逆的,其特征在于在37摄氏度的T?为协会的2.2分钟(在配体浓度为39 pM),并通过T?6-Fluoro-A-85380对α 4 β 2 * 亚型的选择性明显高于其他主要哺乳动物烟碱受体亚型:α 7、α 3 β 4和肌肉型。这些结果表明,6 [F-18]fluoro-A-85380是脑α 4 β 2 * 烟碱受体体内成像的有前景的放射性配体。 在对吸烟的精神分裂症患者的脑组织的研究中发现,与精神健康的吸烟者的脑组织相比,烟碱乙酰胆碱受体的上调较少。由于精神分裂症患者经常长期服用典型或非典型的精神抑制剂,因此在大鼠中测试了这些药物对尼古丁上调α 4 β 2 * 烟碱受体的影响。文献报告表明,典型的精神抑制剂氟哌啶醇没有效果。我们使用5-[I-125]碘-A-85380体外试验检测了非典型精神抑制剂利培酮和奥氮平对大鼠丘脑、纹状体和海马中尼古丁上调这些受体的影响。这两种药物都没有减弱尼古丁的作用,尼古丁分别使这些区域的受体密度增加了50%、80%和90%;然而,在没有尼古丁的情况下给予利培酮,纹状体中的烟碱受体密度适度增加(25%)。 大量轶事证据表明,尼古丁可能是非法使用毒品的入门药物。因此,我们利用药物奖励的动物行为模型,条件性位置偏好(CPP)来检验尼古丁对不同类别的滥用药物(特别是阿片类药物、兴奋剂和大麻)产生行为交叉敏感的假设。在大鼠中进行的这些实验表明,尼古丁预处理可在停用尼古丁后至少3至5天内增强苯丙胺的奖励效应,该效应在19天内消失。潜在的机制涉及α 4 β 2 nAChR,因为竞争性α 4 β 2拮抗剂二氢β赤藓定有效地阻断了尼古丁诱导的交叉致敏的发展。有趣的是,在大鼠中,α 7烟碱拮抗剂methylylycaconitine在不阻断尼古丁自我给药的剂量下也可拮抗交叉致敏作用。本研究和已发表的报告明确表明,尼古丁对阿片类药物和精神兴奋剂的奖励作用产生交叉致敏作用,并使用CPP进行测量。对这些药物的奖励作用的交叉致敏的发展涉及尼古丁与α 4 β 2和α 7 nAChR两者的相互作用,这不同于尼古丁自我给药,其主要由α 4 β 2受体介导。

项目成果

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ALANE S KIMES其他文献

ALANE S KIMES的其他文献

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{{ truncateString('ALANE S KIMES', 18)}}的其他基金

DEVELOPMENT OF NEW PET AND SPECT RADIOTRACERS AND NEW APPROACHES TO PET DATA
新型 PET 和 SPECT 放射示踪剂的开发以及 PET 数据的新方法
  • 批准号:
    6289613
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
HUMAN BRAIN FUNCTION AND DRUG ABUSE
人脑功能与药物滥用
  • 批准号:
    6431941
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Development Of New Pet And Spect Radiotracers
新型宠物和光谱放射性示踪剂的开发
  • 批准号:
    6535530
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Development Of New Approaches To Neuroimaging with PET a
开发 PET 神经影像新方法
  • 批准号:
    6830622
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Human Brain Function And Drug Abuse
人脑功能与药物滥用
  • 批准号:
    6987761
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Development Of New Approaches To Neuroimaging with PET a
开发 PET 神经影像新方法
  • 批准号:
    6987767
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
BIOCHEMISTRY OF LIGAND GATED ION CHANNELS IMPORTANT TO DRUG ABUSE
对药物滥用很重要的配体门控离子通道的生物化学
  • 批准号:
    6431946
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
A RODENT MODEL FOR CHRONIC METHAMPHETAMINE TOXICITY
慢性甲基苯丙胺中毒的啮齿动物模型
  • 批准号:
    6431958
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
A RODENT MODEL FOR CHRONIC METHAMPHETAMINE TOXICITY
慢性甲基苯丙胺中毒的啮齿动物模型
  • 批准号:
    6289624
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
DEVELOPMENT OF NEW PET AND SPECT RADIOTRACERS AND NEW APPROACHES TO PET DATA
新型 PET 和 SPECT 放射示踪剂的开发以及 PET 数据的新方法
  • 批准号:
    6431947
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

相似国自然基金

聚合铁-腐殖酸混凝沉淀-絮凝调质过程中絮体污泥微界面特性和群体流变学的研究
  • 批准号:
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